Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

Since 2002, governments around the world have spent billions of dollars stockpiling neuraminidase inhibitors such as oseltamivir (Tamiflu®) and zanamivir (Relenza®) in anticipation of an influenza pandemic. The rationale for this investment by public health agencies worldwide was that these drugs would stop the spread of influenza and reduce the risk of developing serious complications from influenza such as pneumonia or hospitalisation.

Questions about the accuracy of these claims and the efficacy of both preparations prompted an international team of researchers, led by Dr Tom Jefferson, a Cochrane Review author and independent epidemiologist based in Rome, Italy, to examine newly available evidence and amalgamate two previously published Cochrane Reviews focusing on the efficacy of these interventions into one comprehensive, updated review, published in the January 2012 issue of The Cochrane Library.

In carrying out this research, the Cochrane team was reluctant to focus their efforts on published trial reports available in scientific journals, because while many trials have been conducted around the world, only a few have been published.

“We identified that a large number of studies, including data from 60% of the people who have been involved in randomised, placebo-controlled phase III treatment trials of oseltamivir, have never been published. This includes the biggest treatment trial ever undertaken on oseltamivir that on its own included just over 1,400 people of all ages,” noted Jefferson. "We are concerned that these data remain unavailable for scrutiny by the scientific community."

Following a public pledge by the manufacturer of oseltamivir, Roche, to make full study reports available to scientific investigators, the Cochrane team decided to focus instead on manufacturers’ clinical study reports (typically submitted to regulators) and regulators’ comments. They called reports and comments “regulatory information”. Availability of documents generated by national and regional regulatory bodies during licensing processes in the UK, USA, continental Europe and Japan, along with partial trial reports from the manufacturer of oseltamivir, Roche, and from the European regulator European Medicines Agency (EMA), enabled the researchers to verify information from the trials.

When the team compared published data with the more complete unpublished trial records, they found apparent inaccuracies in the published record of the trials. For example, while unpublished trial reports mentioned serious adverse events (some even classified as possibly related to oseltamivir), one of the two most cited publications makes no mention of such effects, and the other states “... there were no drug-related serious adverse events”.

Having pieced together information from more than 16,000 pages of clinical trial data and documents used in the process of licensing oseltamivir, the Cochrane team raises critical questions about how well the drug works, as well as about its reported safety profile. While the drug did reduce the time to first alleviation of symptoms by an average of 21 hours, it did not reduce the number of people who went on to need hospital treatment. Results from the reanalysis of data also raise questions about how the drug works as an influenza virus inhibitor.

The Cochrane Review authors conclude that there is an urgent need for independent research on both of these drugs. There is continuing uncertainty about their effects beyond the initial reduction in symptoms, mainly because full access to the data needed has still not been provided. “We believe that until more is known about the mode of action of neuraminidase inhibitors health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug,” concluded Jefferson.

The decision to base the review’s analysis solely on regulatory information, unprecedented in the history of Cochrane Reviews, marked the team’s concern, increasingly shared by the international community, about the quality and reliability of published sources of evidence. Research was funded by the UK National Institute for Health Research Health Technology Assessment (NIHR HTA) programme.

Update, November 2012:
Following publication of the updated Cochrane Review in January 2012, the BMJ has begun a campaign to hold Roche accountable to their public pledge made in December 2009 (and referenced above) to make full study reports available to investigators. In support of this initiative, in October 2012 the BMJ established the Open Data Campaign, which “aims to achieve appropriate and necessary independent scrutiny of data from clinical trials”. This website provides background information on the campaign, and provides access to all correspondence to date between the Cochrane Review team and Roche, as well as inquiries to and responses from the World Health Organization and the Centers for Disease Control about the impact of the review’s findings on recent policy decisions.

GlaxoSmithKline (GSK), the UK’s largest pharmaceutical company, announced its support for the BMJ’s open data campaign in late October. Following this announcement, the Cochrane Review team has entered discussions with GSK for the release of individual-level data relevant to their research on neuraminidase inhibitors, on the basis of no restrictions on the use of any data made publicly available (other than anonymisation, which is required by law in all cases).

As public debate on this issue has continued, the real-world impact of the Cochrane Review is also being documented, including an active and wide-ranging discussion on improving access to clinical trial data on Twitter under the hashtag #ctdata. “This is an unprecedented event which shows the depth of concern at the effects that reporting bias may have on health care,” said Jefferson, commenting on the latest developments on 18 November. “The Tamiflu story has become the most quoted example by the gathering campaign for data sharing.”

Read the Cochrane Review

Related reading

The Tamiflu Timeline, by Holly Millward, UK Cochrane Centre, Storify

Drug data shouldn't be secret by Peter Doshi and Tom Jefferson,The New York Times, 10 April 2012

Clinical trial data for all drugs in current use, by Fiona Godlee, BMJ, 29 October 2012

Tamiflu open data campaign